One-pot synthesis of α-aminophosphonates catalyzed by antimony trichloride adsorbed on alumina

Article abstract of DOI:10.1016/j.tetlet.2008.02.047

SbCl₃ adsorbed on Al₂O₃ is found to be an efficient and recyclable catalyst in promoting three-component coupling reactions of aldehydes (aromatic and aliphatic), amines (aryl amines, aliphatic amines and esters of S-α-amino acids) and dialkylphosphites to afford the corresponding α-aminophosphonates in high yields. The ethyl ester of S-phenylalanine was observed to yield the corresponding α-aminophosphonate with S,S-diastereoisomer formed in dominance over the S,R-diastereoisomer.

Full text of DOI:10.1016/j.tetlet.2008.02.047

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2208–2212
One-pot synthesis of a-aminophosphonates catalyzed
by antimony trichloride adsorbed on alumina
Ambica a, Satish Kumar a, Subhash C. Taneja b, Maninder S. Hundal c, Kamal K. Kapoor a,*
a Department of Chemistry, University of Jammu, Jammu 180 006, India
b Bio-organic Chemistry Division, Indian Institute of Integrative Medicines, Canal Road, Jammu 180 001, India
c Department of Chemistry, Guru Nanak Dev University, Amritsar 143 005, India
Received 1 January 2008; revised 6 February 2008; accepted 11 February 2008
Available online 13 February 2008
Abstract
SbCl3 adsorbed on Al2O3 is found to be an efficient and recyclable catalyst in promoting three-component coupling reactions of
aldehydes (aromatic and aliphatic), amines (aryl amines, aliphatic amines and esters of S-a-amino acids) and dialkylphosphites to afford
the corresponding a-aminophosphonates in high yields. The ethyl ester of S-phenylalanine was observed to yield the corresponding
a-aminophosphonate with S,S-diastereoisomer formed in dominance over the S,R-diastereoisomer.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: SbCl3/Al2O3; a-Amino acid; a-Aminophosphonate; Solid supported reagents; Recyclability
a-Aminophosphonates have been the focus of attention
in recent years because of their structural analogy to the
corresponding a-amino acids as well as heterocyclic phos-
phonates1 and x-aminophosphonates.2 They act as peptide
mimics,3 antibiotics, herbicides,4 pharmacological agents5
and enzyme inhibitors.6 In addition, a-aminophosphonates
have broad application due to their antifungal7 and anti-
bacterial activities.8 There are two main pathways for the
synthesis of a-aminophosphonates:
(b) Pudovik reaction, where dialkylphosphites are added
to imines using either a base21–23 or a Lewis acid such
as AlCl3,24 Me2AlCl,25 BF3,26 SnCl4,27 t-PcAlCl28
and ZrCl4.29
However, in spite of their potential utility, these meth-
ods typically suffer from one or more disadvantages such
as high cost, use of a stoichiometric amount of catalyst,
moisture sensitivity, specialized handling, tedious work-
up and non-recyclability of the catalyst. The use of reagents
impregnated on inorganic supports11,14,30 offers advantages
in preparative procedures, such as simple work-up, easy
handling, mild reaction conditions, cleaner products,
enhanced selectivity, reduction of by-products and
produced waste, much improved reaction rates and recycl-
ability of the catalyst. In continuation of our ongoing
studies30b,31 into the applications of SbCl3 impregnated
on inorganic supports as a post transitional Lewis acid in
organic synthesis, we wished to explore the usage of
SbCl3/Al2O3 for the synthesis of a-aminophosphonates
and a-aminophosphonates of the esters of a-amino acids
(S-phenylglycine and S-phenylalanine).
(a) Kabachnik–Fields three-component reaction in
which an amine, an aldehyde and a di- or tri-
alkylphosphite are reacted in a single-pot in the pres-
ence of a catalyst such as LiClO4,9,10 TaCl5–SiO2,11
InCl3,12 Sc(O3SOC12H25)3,13 SiO2/NH4HCO3,14 lan-
thanide–triflate,15 CF3CO2H,16 Mg(ClO4)2,17 TiCl4,18
PhMe3NCl19 and In(OTf)3.20
*
Corresponding author. Tel.: +91 191 245 3969; fax: +91 191 245 3079/
243 1365.
E-mail address: k2kapoor@yahoo.com (K. K. Kapoor).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.047

Ambica et al. / Tetrahedron Letters 49 (2008) 2208–2212
2209
O
CHO
NH2
OMe
OMe
P
H
SbCl3/Al2O3
CH3CN
+
+
O P
OMe
OMe
H2O
+
N
H
1a
Scheme 1. Preparation of a-aminophosphonate 1a in the presence of SbCl3/Al2O3.
A
mixture of benzaldehyde (10 mmol), aniline
cases, the major diastereoisomer crystallized from the
viscous oil on cooling in a refrigerator. The crystalline
product 1z obtained in the reaction between S-phenylala-
nine ethyl ester and p-chlorobenzaldehyde was assigned
the S,S-configuration on the basis of X-ray analysis.32c
(Fig. 2).
(10 mmol) and dimethylphosphite (12 mmol) in acetonitrile
(65 mL) was stirred at room temperature in the presence of
5 mol % of SbCl3/Al2O3 and 5 A molecular sieves (Scheme
˚
1) to yield the expected a-aminophosphonate 1a10 in 3 h.
The above experiment was carried out with 5 mol % of
SbCl3 and it was found that the reaction took longer
(5 h) to reach completion. No product formation was
observed in the presence of Al2O3 even after 8 h of stir-
ring at room temperature. It seems that Al2O3 acts only
as a support for the reaction. It was considered appropri-
ate to employ SbCl3/Al2O3 in future studies in view of
the recyclability of SbCl3 adsorbed on an inorganic sup-
port (hydroxyapatite, HAP).30b In order to investigate the
recyclability, SbCl3/Al2O3 was recovered, activated at
110 °C in an oven and reused ten times, successively, for
the reaction of benzaldehyde, aniline and dimethylphos-
phite; no significant decrease in its activity was noticed
(Fig. 1).
The structure is stabilized by two hydrogen bonds
(Fig. 3) between the hydrogen attached to the amine nitro-
gen (N1) and the phosphonate oxygen (O1i) belonging to
the symmetry related molecule (where i = ꢀx + 1, ꢀy,
i
˚
ꢀz). The N1–H1ꢁ ꢁ ꢁO1 distance is 2.053(4) A and the
N1–H1ꢁ ꢁ ꢁO1 angle is 168.1(2)°. The amine hydrogen of this
symmetry related molecule forms an identical H-bond with
molecule (x,y,z) to give a tight H-bonded dimer (Fig. 3).
In summary, SbCl3/Al2O3 is found to be an efficient
catalyst for the synthesis of a-aminophosphonates. SbCl3/
Al2O3 is stable, easy to handle, recoverable by simple filtra-
tion and is recyclable.
General procedure: A mixture of amine (10.0 mmol),
˚
A range of aldehydes underwent reactions with aromatic
and aliphatic amines including a secondary amine (entry
16) to give the corresponding a-aminophosphonates. The
results are summarized in Table 1.
We next focused our attention on the esters of a-amino
acids (Scheme 2). For the ethyl esters of S-phenylglycine
and S-phenylalanine, the formation of 9:1 and 3:2 mixtures
of diastereoisomers was evident upon analyzing the 1H
NMR spectra of the viscous oils obtained by column
chromatography over silica gel. Interestingly, in all the
aldehyde (10.0 mmol), dialkylphosphite (12.0 mmol), 5 A
31
molecular sieves (200 mg) and SbCl3/Al2O3
(3.1 g,
5 mol % with respect to the amount of SbCl3) in CH3CN
(65 mL) was stirred at room temperature for the appropri-
ate amount of time (Table 1). After completion of the reac-
tion (TLC), CH3CN was distilled off under reduced
pressure and the residue was diluted with EtOAc (70 mL)
and filtered to remove solid materials. The filtrate was
washed with water (2 ꢂ 20 mL) and brine (20 mL). The
organic layer was dried over anhydrous Na2SO4 and con-
91
90
89
88
87
86
85
84
83
1
2
3
4
5
6
7
8
9
10
No. of times catalyst used
Fig. 1. Results of recycling the catalyst.

2210
Ambica et al. / Tetrahedron Letters 49 (2008) 2208–2212
Table 1
One-pot synthesis of a-aminophosphonates catalyzed by SbCl3/Al2O3
Entry
Aldehyde
Amine
Phosphitea
Productb
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Benzaldehyde
Benzaldehyde
Aniline
Aniline
Aniline
Aniline
Benzylamine
Aniline
Benzylamine
Aniline
p-Toluidine
p-Toluidine
Aniline
DMP
DEP
DEP
DEP
DEP
DEP
DEP
DEP
DMP
DEP
DMP
DMP
DMP
DEP
DMP
1a10
1b17
1c
3
3
3.5
4
2.5
5
90
91
90
82
83
75
90
92
84
86
49
88
83
77
89
p-Tolualdehyde
3,4,5-Trimethoxybenzaldehyde
p-Nitrobenzaldehyde
trans-Cinnamaldehyde
Benzaldehyde
1d
1e
1f
1g
1h17
3
p-Anisaldehyde
p-Anisaldehyde
3.5
3.5
3.5
7.0
4.5
4.5
5.0
3.0
1i
p-Tolualdehyde
Butyraldehyde
p-Tolualdehyde
p-Tolualdehyde
p-Anisaldehyde
1j
1k
1l
Aniline
Benzylamine
2-Aminopyridine
Aniline
1m
1n
m-Anisaldehyde
1o
Cl
O
P
OMe
OMe
16
p-Chlorobenzaldehyde
Piperidine
DMP
4.0
84
N
1p
17
18
19
20
21
22
23
24
25
26
a
o-Chlorobenzaldehyde
o-Chlorobenzaldehyde
p-Chlorobenzaldehyde
p-Chlorobenzaldehyde
p-Tolualdehyde
Benzaldehyde
p-Chlorobenzaldehyde
p-Anisaldehyde
Aniline
Aniline
Aniline
Aniline
DMP
DEP
DMP
DEP
DMP
DMP
DMP
DMP
DMP
DMP
1q
3.0
3.5
2.5
2.5
5
4.5
5
4.5
5.5
5
92
90
91
91
65
74
78
73
68
65
1r
1s17
1t
2-Aminobenzothiazole
Ethyl ester of S-phenylglycinec
Ethyl ester of S-phenylglycinec
Ethyl ester of S-phenylglycinec
Ethyl ester of S-phenylalaninec
Ethyl ester of S- phenylalaninec
1u
1vd
1wd
1xd
1ye
1ze
Benzaldehyde
p-Chlorobenzaldehyde
DMP = dimethyl phosphite and DEP = diethyl phosphite.
All new compounds gave satisfactory spectral data (1H and 13C NMR, MS).
Reactions (entries 22–26) were carried out at reflux.
9:1 mixture of diastereoisomers as calculated from the 1H NMR spectrum of the crude product.
3:2 mixture of diastereoisomers as calculated from the 1H NMR spectrum of the crude product.
b
c
d
e
centrated under reduced pressure to afford a crude product,
which on passing through a silica (60–120 mesh) column
using EtOAc–petroleum ether as an eluent gave the pure
a-aminophosphonates. The structures of the products were
established by spectroscopy.
For the esters of a-amino acids: To a solution of
10.0 mmol of the ester of the a-amino acid hydrochloride
in 80 mL of water at 0 °C was added aqueous ammonia
solution (25% NH3) dropwise with stirring until the solu-
tion became neutral. The mixture was extracted with
CHCl3 (4 ꢂ 30 mL) and the combined CHCl3 layers were
washed with brine (40 mL), dried over anhydrous Na2SO4
and the solvent evaporated under reduced pressure to
afford the ester of the a-amino acid, which was converted
to the corresponding aminophosphonates following the
general procedure.
With a-amino acid esters, better yields were obtained
using 1.1 equiv of the aldehyde with respect to the amount
OMe
CO2Et
O
P
OMe
EtO2C
NH2
CHO
N
n
n
H
H
SbCl3/Al2O3
CH3CN
R
+ O
P
+
H2O
OMe
+
OMe
n = 0, 1
R = H, p-Cl, p-OMe
R
Scheme 2. a-Aminophosphonates of the esters of a-amino acids in the presence of SbCl3/Al2O3.

Ambica et al. / Tetrahedron Letters 49 (2008) 2208–2212
2211
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Fig. 3. H-bonding between phosphonate oxygen (O1) and the amino
hydrogen (H1) attached to nitrogen (N1). Hydrogen atoms attached to
carbon atoms are not shown.
32. The physical and spectroscopic data of the selected compounds is as
follows:
of ester. MeOH–CHCl3 was used as an eluent for column
chromatography of the products in these cases.
(a) Compound 1u: Yellowish, crystalline; mp: 174–175 °C. IR, mmax
/
cmꢀ1 (KBr): 3217, 3016, 1596, 1538, 1443, 1250. 1H NMR: (CDCl3,
3
300 MHz) d 2.31 (s, 3H, CH3), 3.55 (d, 3H, JHP = 10.5 Hz, OCH3),
Acknowledgement
3
2
3.81 (d, 3H, JHP = 10.8 Hz, OCH3), 5.58 (d, 1H, JHP = 21.9 Hz,
CH), 7.02–7.22 (m, 4H, Ar-H), 7.33–7.54 (m, 4H, Ar-H). 13C NMR:
(CDCl3, 75 MHz) d 21.7, 54.6, 56.6, 119.8, 121.2, 122.3, 126.3, 127.6,
128.8, 129.9, 131.7, 132.4, 138.6, 152.5, 166.4. Anal. Calcd for
The authors are thankful to DST, Govt. of India, New
Delhi for Project Grant No. SR/S1/OC-36/2004.
C
17H19N2O3PS (362.384): C, 56.35: H, 5.28: N, 7.73: S, 8.85. Found:
C, 56.35: H, 5.29: N, 7.72: S, 8.84. MS (ESI) m/z: 362.9 (M+H)+.
(b) Compound 1v: White, crystalline; mp: 76–78 °C. IR, mmax/cmꢀ1
References and notes
(KBr): 3267, 2954, 1738, 1599, 1490, 1454, 1243. 1H NMR: (CDCl3,
3
1. Moonen, K.; Laureyn, I.; Stevens, C. V. Chem. Rev. 2004, 104,
200 MHz)
d
1.15 (t, 3H, JHH = 7.1 Hz, CH3), 3.62 (d, 3H,
3JHP = 11.5 Hz, OCH3), 3.75 (d, 3H, JHP = 10.5 Hz, OCH3),
3
6177.

2212
Ambica et al. / Tetrahedron Letters 49 (2008) 2208–2212
3JHP = 10.5 Hz, OCH3), 3.69 (d, 3H, JHP = 10.6 Hz, OCH3), 4.10
3
4.10–4.31 (m, 4H, CHCO2Et, CHPO3Me2, CH2), 7.27–7.41 (m, 10H,
Ar-H). 13C NMR: (CDCl3, 50 MHz) d 13.2, 53.1, 56.5, 59.3, 60.3,
61.9, 126.3, 126.7, 127.0, 127.3, 127.5, 133.5, 133.7, 136.2, 171.8. Anal.
Calcd for C19H24NO5P (377.371): C, 60.47: H, 6.41: N, 3.71. Found:
C, 60.47: H, 6.40: N, 3.72.
(d, 1H, JHP = 18.2 Hz, CHPO3Me2), 4.13 (q, 2H, JHH = 7.1 Hz,
CH2CH3), 6.95–7.27 (m, 9H, Ar-H). 13C NMR: (CDCl3, 50 MHz) d
14.3, 39.7, 53.8, 57.7, 58.9, 59.9, 61.0, 126.9, 128.4, 128.7, 129.5, 130.0,
133.1, 133.9, 137.3, 173.6. Anal. Calcd for C20H25ClNO5P (425.843):
C, 56.41: H, 5.92: N, 3.29. Found: C, 56.42: H, 5.93: N, 3.28. MS
(ESI) m/z: 428.1 (30) and 426.1 (100) (M+H)+.
2
3
MS (ESI) m/z: 378.2 (M+H)+.
20
(c) Compound 1z: White, crystalline mp: 65 °C; ½aꢃD 0, c 1 in
20
chloroform X-ray crystallographic details: C20H25ClNO5P, formula
2nd diastereoisomer: Viscous oil; ½aꢃD ꢀ23.54, c 1 in chloroform; IR,
max/cmꢀ1 (neat): 3259, 2959, 1736, 1597, 1492, 1458, 1247. 1H NMR:
˚
˚
ꢀ
˚
weight = 425.83, k = 0.71069 A, triclinic, P1 (number 2),
a = 10.256(5) A, b = 10.583(5) A, c = 11.097(5) A, a = 81.940(5)°,
m
3
˚
(CDCl3, 200 MHz) d 1.02 (t, 3H, JHH = 7.1 Hz, CH3), 2.87 (m, 2H,
CH2Ph), 3.48 (d, 3H, JHP = 10.5 Hz, OCH3), 3.56 (dd, 1H,
3JHH = 5.9 Hz, 7.8 Hz, CHCO2Et), 3.60 (d, 3H, JHP = 10.6 Hz,
3
3
˚
b = 78.030(5)°, c = 67.740(5)°, V = 1087.9(9) A , Z = 2, qcalc
=
1.300 Mg/m3, l = 0.279 mmꢀ1, F(000) = 448, reflections collected =
4308, full-matrix least-squares on F2, parameters = 253, R1 = 0.0807,
wR2 = 0.1987, largest difference in peak and hole (0.475 and
3
3
OCH3), 3.87 (q, 2H, JHH = 7.1 Hz, CH2CH3), 3.88 (d, 1H,
2JHP = 19.7 Hz, CHPO3Me2), 6.96–7.27 (m, 9H, Ar-H). 13C
NMR: (CDCl3, 50 MHz) d 13.9, 39.2, 53.6, 58.8, 59.8, 60.9, 61.6,
126.9, 128.4, 128.6, 129.5, 129.9, 133.1, 133.9, 137.2, 173.6.
Anal. Calcd for C20H25ClNO5P (425.843): C, 56.41: H, 5.92: N,
3.29. Found: C, 56.42: H, 5.93: N, 3.28. MS (ESI) m/z: 428.1 (30) and
426.1 (100) (M+H)+.
ꢀ0.336 e Aꢀ3). CCDC number: 662851; IR, mmax/cmꢀ1 (KBr): 3259,
˚
2959, 1736, 1597, 1492, 1458, 1247. 1H NMR: (CDCl3, 200 MHz) d
3
1.20 (t, 3H, JHH = 7.1 Hz, CH3), 2.79 (dd, 1H, JHH = 13.5 Hz,
8.8 Hz, CHaHbPh), 2.98 (dd, 1H, JHH = 13.5 Hz, 5.2 Hz, CHaHbPh),
3
3.22 (dd, 1H, JHH = 8.7 Hz, 5.3 Hz, CHCO2Et), 3.61 (d, 3H,